1. Field of the Invention
The present invention relates to monoclonal antibodies and an agent containing the same, more particularly, the present invention pertains to a monoclonal antibody capable of preferentially recognizing arteriosclerotic lesions and bonding thereto and an agent for detecting and treating arteriosclerosis, containing at least one of such monoclonal antibodies.
2. Description of the Prior Art
The atherosclerosis is a localized sclerogenous lesion developed principally in large or middle sized arterias such as abdominal aorta, coronary artery, encephaloartery, renal artery, cerebral artery and is a major cause for various kinds of infarction such as myocardial infarction, cerebral infarction. The reason why such diseases are caused has not yet been demonstrated clearly. It can be said that, in the case of aorta, a normal aorta has the three layer-structure comprising an internal membrane (tunica intima) composed of endothelial cells, a tunica media composed of the elastica and the smooth muscle of the tunica media and a tunica externa composed of elastica. In this respect, it has been reported that the following materials are accumulated therein. As the materials accumulated, there may be mentioned such as lipids, for example, cholesterol ester, phospholipids; mucopolysaccharides; blood components such as apo-LDL (low density lipo-protein) which is a main protein of LDL in plasma; fibrous tissues or the like.
As is well known, the formation of a hypertrophic portion is one of the most characteristic properties of the atherosclerosis and it has been reported that the following phenomena are taken place at that portion:
(i) the migration and proliferation of smooth muscle cells of the tunica media; PA0 (ii) the formation of foam cells taking up a large amount of lipids therein; PA0 (iii) the deposition of lipids at the exterior of cells; PA0 (iv) the formation of the thrombus; etc.
The diseases caused due to the presence of the atherosclerosis, such as coronal arteriosclerosis, arteriocapillary sclerosis are developed in even younger people and gradually proceed. Moreover, when the disease is realized, the lesion thereof is established and causes patients to die in the worst case. Therefore, it seems to be more preferable to detect the presence of such lesions in the earliest stage and regress atherosclerosis. For this purpose, it is needed to have an excellent method for detecting the development of these diseases in the human body, with high accuracy and safety.
As a conventional method for detecting diseases caused by atherosclerosis, for instance, arteriosclerosis, there have been proposed (i) an echography technique in which the proliferation velocity or the reflective waves of ultrasonics is used to detect the presence of lesions or (ii) an angiography technique in which an angiogram obtained is analyzed to detect the presence of lesions. In these methods, the human body is directly examined. While, as indirect methods for diagnosis, there may be mentioned such as a method comprising collecting blood from a human body to be examined, analyzing the blood to obtain information on the amount of cholesterol and lipoprotein and on the coagulative factors and then estimating the probability whether arteriosclerotic lesions are present or not.
However, the method (i) is not sufficient in its accuracy because of its low resolution and the method (ii) needs a skilled person for operating the machine since it contains complicated operations for driving the same and possibly causes damage on the body of the patients examined. In addition, the latter indirect method also has disadvantages such that the accuracy thereof is not high enough to determine whether the person examined suffers from such disease or not, since the method does not examine arteriosclerotic lesions per se and further it is not clearly demonstrated if there is an exact mutual relation between the estimated probability and the presence of arteriosclerotic lesions in the body examined.
For this purpose, there is a strong need for developing a new method for detecting the presence of lesions in a human body, which has a high specificity to the lesions and a high safety in applying it to the human body and can easily be carried out without skillfullness. However, up to now, there is proposed no such effective tool.
Referring now to the method for treating these diseases, it is currently adopted to administrate an agent such as heparin, warfarin as the anticoagulant or clofibrate as the decholesterolization agent or an antilipemic agent while simultaneously adopting the dietotherapy.
Among the agents for treating the diseases, the antilipemic agent is used to simply lower the concentration of lipids of patients suffering from hyperlipidemia and it does not directly affect arteriosclerotic lesions. Furthermore, it is not clear whether the decrease in the lipid concentration due to the administration of an antilipemic agent is effective to treat patients suffering from arteriosclerosis or not.
From the foregoing description, it is quite clear that there is no effective therapeutic agent for curing the disease mentioned above. This is because, in the treatment proposed previously, an agent which directly affects the arteriosclerotic lesions is not used at all and such treatment is effective only to reduce the degree of risk.
Under such circumstances, there is also a strong need for developing an agent which directly affects arteriosclerotic lesions caused due to the presence of atherosclerosis.
U.S. Pat. No. 4,619,895 to S. Cubicciotti et al., disclosed a lipoprotein marker for type IV hypertriglyceridemia using a monoclonal antibody capable of specifically binding to a characteristic epitoptic site on LDL subspecies. French Patent No. 1,531,058 discloses immunochemical determination of substances specific for atherosclerosis by using a polyclonal antibody which is prepared by a method described in Med. Klin., 61, 208 (1966).
Recently, G. Kohler and C. Milstein proposed a hybridoma technique for preparing a monoclonal antibody having a specificity to a specific antigenic determinant of the sheep red cell membrane by cultivating an antibody-producing B cell hybridoma which is obtained by fusing spleen cells of mouse immunized with SRC (sheep red cell) and myeloma cells [see, Nature (Lond.), 1975, 256, 495-497]. In addition, Proc. Nath. Acad. Sci. U.S.A., 1982, 79, 7929-7933, S. C. Fujita et al. discloses that such hybridoma technique may be applied to produce monoclonal antibodies against specific materials separated from a complex mixture of immunogens.
Such hybridoma technique has drawn great attention since these reports present a high possibility to carry out diagnosis and treatment for various kinds of diseases utilizing monoclonal antibodies having a property such that it may specifically react with specific material closely correlating to an interested disease.
Then, if a monoclonal antibody which preferentially recognizes arteriosclerotic lesions and is specifically bonded to antigens originated from lesions interested are produced according to the same procedures as mentioned above (hybridoma technique), a new method for detecting the arteriosclerotic lesions and a new medicine for treating patients suffering from these diseases would be established.
Unfortunately, it is not possible to produce a monoclonal antibody from arteriosclerotic lesions according to the conventional procedure in which cells isolated from a specific tissue, for example, foam cells are used. In addition, it is considered to be more effective to use the whole lesion, in order to produce a monoclonal antibody which is specific to various kinds of lesions of arteriosclerosis. However, such procedure has not yet been developed and the monoclonal antibody specifically reacting with the arteriosclerotic lesions has not yet been proposed.